Fatty acid amide hydrolase (FAAH) has emerged as a potential target for developing analgesic, anxiolytic, antidepressant, sleep-enhancing, and anti-inflammatory drugs, and tremendous efforts have been made to discover potent and selective inhibitors of FAAH. Most known potent FAAH inhibitors described to date employ covalent mechanisms, inhibiting the enzyme either reversibly or irreversibly. Recently, a benzothiazole-based analogue (1) has been described possessing a high potency against FAAH yet lacking a structural feature previously known to interact with FAAH covalently. However, covalent inhibition of FAAH by 1 has not been fully ruled out, and the issue of reversibility has not been addressed. Confirming previous reports, 1 inhibited recombinant human FAAH (rhFAAH) with high potency with IC(50) ~2 nM. It displayed an apparently noncompetitive and irreversible inhibition, titrating rhFAAH stoichiometrically within normal assay times. The inhibition appeared to be time dependent, but the time dependence only improved potency by a small degree (from ~8 to ~2 nM). However, mass spectrometric analyses of the reaction mixture failed to reveal any cleavage product or covalent adduct and showed full recovery of the parent compound, ruling out covalent, irreversible inhibition. Dialysis revealed recovery of enzyme activity from enzyme-inhibitor complex over a prolonged time (>10 h), demonstrating that 1 is indeed a reversible, albeit slowly dissociating inhibitor of FAAH. Molecular docking indicated that the sulfonamide group of 1 could form hydrogen bonds with several residues involved in catalysis, thereby mimicking the transition state. The long residence time displayed by 1 does not appear to derive exclusively from great thermodynamic potency and is consistent with an increased kinetic energy barrier that prevents dissociation from happening quickly.
The dynamics and flexibility of protein-ligand complexes is central to understanding and predicting binding geometries and energetics. We have calculated various measures of the dynamic flexibility of a pseudo-C2-symmetric protein, HIV-1 protease, complexed with the asymmetric inhibitor KNI-272 based on molecular dynamics simulations. This system is expected to be an excellent candidate for observing asymmetric dynamics between the two monomers due to the differences in the interactions between the two monomers of the protease and the inhibitor. Experimental methods have thus far been unable to observe the expected asymmetry in this system. Our calculated results are in excellent agreement with the available experimental data for the mainchain order parameters from a parallel 15 N NMR study of the same inhibitor-protein complex, as well as the Debye-Waller temperature factors from X-ray crystallography. In our simulations, asymmetry between the monomers is found almost exclusively in the side-chain order parameters of the inhibitor and protease (especially residues 84A and 84B), for which experimental data are not yet available. We analyze the dynamic information obtained from the different methods and discuss protein-ligand interactions responsible for the dynamical behavior of the complex.
An analysis of molecular shape has been performed along an ab initio reaction path of the PPO + OPP isomerization. In a first apFroximation, we have used the fused-sphere (van der Waals) model to represent shape. The results show that there is no one-to-one correspondence between the species defined in terms of shape and those based on an energy criterion. In contrast to the cases of most other isomerizations in triatomic molecules (e.g., the HCN isomerization), for the PPO isomerization there exists a stable intermediate. For the elementary reaction from the linear PPO (C,,, reactant) to the cyclic P20 (CzV, intermediate), we found no distinct molecular shape type for the transition structure (between the reactant and the intermediate). In terms of shape, the nuclear configuration of the transition structure is more similar to that of the intermediate than that of the reactant. Using the PPO -+ OPP reaction as an example, in this work we discuss the implications of this result regarding possible measures of shape similarity and shape stability along reaction paths. We have performed a molecular-shape analysis of the electron density contour surfaces to test the reliability of the fused-sphere approximation. A comparison between the van der Waals and electron isodensity surface models at critical points shows that the former model can be qualitatively correct for molecular-shape descriptions along some reastion paths.
Potential energy surfaces can be classified into combinatorial equivalence classes, based on their partitioning into catchment regions. Two classification theorems are proven: one for reaction spheres and another for reaction tori. A method for constructing all possible equivalence classes of reaction spheres and reaction tori is presented. As illustration of the general results, it is shown that not all the two-dimensional reaction spheres are combinatorially equivalent to polyhedra in the three-dimensional Euclidean space. As examples, several reaction spheres are calculated by using the RHF method at the 3 -2 1~* level, describing the interactions between a series of polyatomic ions and H'. The calculations show that the potential energy surface of the C0:-. . . Ht interaction, combinatorially equivalent to that of the NO;. . . H t interaction, is not combinatorially equivalent to any polyhedron in 3-space; however, the combinatorially different potential energy surface of the PO:-.. . H' interaction is equivalent to a polyhedron in 3-space.The topological classification scheme is proposed for the study of similarities between various families of chemical reactions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.